The primary response of T-cells, involving T-cell activation, expansion, and differentiation is essential for the initiation of an immune response to a foreign antigen. The activation of T-cells by antigen presenting cells (APCs) requires at least two separate signals (K. E. Hellstrom et al. (1996) Cancer Chemother. Pharmacol. 38:S40-1; N. K. Damle et al. (1992) J. Immunol. 148:1985-92; J. M. Green et al. (1994) Eur. J. Immunol. 24:265-72; E. C. Guinan et al. (1994) Blood 84:3261-82; J. W. Hodge et al. (1995) Cancer Res. 55:3598-603). The first signal causes T-cell entry into the cell cycle, and is mediated by foreign antigens presented by the major histocompatibility complex (MHC). The second signal, termed costimulation, causes cytokine production and T-cell proliferation, but is neither antigen-specific, nor MHC restricted (R. H. Schwartz (1990) Science 248:1349-1356).
Costimulation is believed to be mediated by one or more distinct cells surface molecules expressed by APCs (M. K. Jenkins et al. (1988) J. Immunol. 140:3324-3330; P. S. Linsley et al. (1991) J. Exp. Med. 173:721-730; C. D. Gimmi, et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575-6579; J. W. Young et al. (1992) J. Clin. Invest. 90:229-237; L. Koulova et al. (1991) J. Exp. Med. 173:759-762; H. Reiser et al. (1992) Proc. Natl. Acad. Sci. USA 89:271-275; G. A. van-Seventer et al. (1990) J. Immunol. 144:4579-4586; J. M. LaSalle et al. (1991) J. Immunol. 147:774-80; M. I. Dustin et al. (1989) J. Exp. Med. 169:503; R. J. Armitage et al. (1992) Nature 357:80-82; Y. Liu et al. (1992) J. Exp. Med. 175:437-445). Considerable evidence suggests that B7, an APC cell-surface protein, is one such costimulatory molecule (P. S. Linsley et al. (1991) J. Exp. Med. 173:721-730; C. D. Gimmi et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575-6579; L. Koulova et al. (1991) J. Exp. Med. 173:759-762; H. Reiser et al. (1992) Proc. Natl. Acad. Sci. USA 89, 271-275; P. S. Linsley et al. (1990) Proc. Natl. Acad. Sci. USA 87:5031-5035; G. J. Freeman et al. (1991) J. Exp. Med. 174:625-631).
B7 has been shown to bind to two counter-receptors (ligands) expressed on T-cells, termed CD28 and CTLA-4. B7 binding to CD28 induces T-cells to proliferate and secrete IL-2 (P. S. Linsley et al. (1991) J. Exp. Med. 173, 721-730; C. D. Gimmi et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575-6579; C. B. Thompson et al. (1989) Proc. Natl. Acad. Sci. USA 86:1333-1337; C. H. June et al. (1990) Immunol. Today 11:211-6; F. A. Harding et al. (1992) Nature 356:607-609), allowing full T-cell activation. Conversely, B7 binding to CTLA-4 mediates T-cell down-regulation. The importance of the B7:CD28/CTLA-4 costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this pathway results in the development of antigen specific tolerance in murine and humans systems (F. A. Harding et al. (1992) Nature 356:607-609; D. J. Lenschow et al. (1992) Science 257:789-792; L. A. Turka et al. (1992) Proc. Natl. Acad. Sci. USA 89:11102-11105; C. D. Gimmi et al. (1993) Proc. Natl. Acad. Sci. USA 90:6586-6590). Conversely, the ectopic expression of B7 in B7 negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge (L. Chen et al. (1992) Cell 71:1093-1102; S. E. Townsend et al. (1993) Science 259:368-370; S. Baskar et al. (1993) Proc. Natl. Acad. Sci. USA 90:5687-5690). Therefore, manipulation of the B7:CD28/CTLA-4 pathway offers great potential to stimulate or suppress immune responses in humans.
In addition to the previously characterized B7 molecule (referred to hereafter as B7-1) B7-1-like molecules have been identified (see, e.g., M. Azuma et al. (1993) Nature 366:76-79; C. Chen et al. (1994) J. Immunol. 152:4929-36; R. H. Reeves et al. (1997) Mamm. Genome 8:581-582; K. Ishikawa et al. (1998) DNA Res. 5:169-176; U.S. Pat. No. 5,942,607 issued Aug. 24, 1999 to Freeman et al.). In particular, PD-L1 and PD-L2 have been identified as inhibitors of T-cell activation (G. J. Freeman et al. (2000) J. Exp. Med. 192:1027-1034; Y. Latchman et al., (2001) Nature Immunology 2:261-268), whereas B7-H1, B7-H3, and B7-DC have been described as co-stimulators of T-cell proliferation (H. Dong et al. (1999) Nature Medicine 5:1365-1369; A. I. Chapoval (2001) Nature Immunology 2:269-274; Tseng et al. (2001) J. Exp. Med, 193(7):839-45).
Thus, there is a growing family of factors related to B7-1, which modulate T-cell activation (reviewed by J. Henry et al. (1999) Immunol. Today 20:285-288). The identification, isolation, and characterization of B7-related factors are therefore important goals for the further understanding of T-cell activation and function in both normal and disease states in animals, particularly humans. Accordingly, the present invention discloses the discovery and characterization of three B7-related factors, termed BSL1, BSL2, and BSL3. Also disclosed are various assays and treatments utilizing the BSL1, BSL2, and BSL3 factors.